Stereospecific total synthesis of the indole alkaloid ervincidine. Establishment of the C-6 hydroxyl stereochemistry

Article abstract of DOI:10.1021/jo402692u

The total synthesis of the indole alkaloid ervincidine (3) is reported. This research provides a general entry into C-6 hydroxy-substituted indole alkaloids with either an α or a β configuration. This study corrects the errors in Glasby's book (Glasby, J. S. Encyclopedia of the Alkaloids; Plenum Press: New York, 1975) and Lounasmaa et al.'s review (Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1999; Vol. 52, pp 103-195) as well as clarifies the work of Yunusov et al. (Malikov, V. M.; Sharipov, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin. 1972, 8, 760-761. Rakhimov, D. A.; Sharipov, M. R.; Aripov, Kh. N.; Malikov, V. M.; Shakirov, T. T.; Yunusov, S. Yu. Khim. Prir. Soedin. 1970, 6, 724-725). It establishes the correct absolute configuration of the C-6 hydroxyl function in ervincidine. This serves as a structure proof and corrects the misassigned structure reported in the literature.

Full text of DOI:10.1021/jo402692u

Article
pubs.acs.org/joc
Stereospecific Total Synthesis of the Indole Alkaloid Ervincidine.
Establishment of the C‑6 Hydroxyl Stereochemistry
Sundari K. Rallapalli,† Ojas A. Namjoshi,† V. V. N. Phani Babu Tiruveedhula,† Jeffrey R. Deschamps,‡
and James M. Cook*,†
†Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
‡Center for Biomolecular Science and Engineering, Naval Research Laboratory, Code 6930, Washington, DC 20375, United States
S
* Supporting Information
ABSTRACT: The total synthesis of the indole alkaloid
ervincidine (3) is reported. This research provides a general
entry into C-6 hydroxy-substituted indole alkaloids with either
an α or a β configuration. This study corrects the errors in
Glasby’s book (Glasby, J. S. Encyclopedia of the Alkaloids;
Plenum Press: New York, 1975) and Lounasmaa et al.’s review
(Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA,
1999; Vol. 52, pp 103−195) as well as clarifies the work of
Yunusov et al. (Malikov, V. M.; Sharipov, M. R.; Yunusov, S.
Yu. Khim. Prir. Soedin. 1972, 8, 760−761. Rakhimov, D. A.;
Sharipov, M. R.; Aripov, Kh. N.; Malikov, V. M.; Shakirov, T. T.; Yunusov, S. Yu. Khim. Prir. Soedin. 1970, 6, 724−725). It
establishes the correct absolute configuration of the C-6 hydroxyl function in ervincidine. This serves as a structure proof and
corrects the misassigned structure reported in the literature.
reported the structure of ervincidine as similar to that of the
polyneuridine subclass with four stereocenters, C-3 (S), C-5 (R),
C-15 (R), and the hydroxymethyl function in the β configuration
at C-16 (S). However, the stereochemistry of the C-6 alcohol was
not assigned in this report as well. As illustrated in Figure 1, in the
proposed structure of ervincidine by Glasby1 and Lounasmaa
et al.,5 the hydroxymethyl group at C-16 was assigned the α stereo-
chemistry, while, according to Yunusov et al.,4 the hydroxy-
methyl group at C-16 was proposed to have the β stereo-
chemistry. The stereochemistry and the structure of ervincidine
especially with regard to the C-6 and C-16 stereocenters
stimulated interest in this alkaloid. The total synthesis of this
natural product was also necessary because the only information
known in the literature3,4 was the optical rotation of the isolated
indole alkaloid ervincidine (3), which was reported as +29.5°
(c 0.6, MeOH) by Yunusov et al.3,4 No unequivocal spectral
information or elemental analysis had been reported. Addition-
ally, the stability of the C-6 hydroxyl function had not been
explored in the literature. The aim of this report was hence
centered on the stereospecific total synthesis of the indole
alkaloid ervincidine and correction of the stereochemical
ambiguity reported in the literature.2−5 Moreover, the design
of a synthetic entry into the C-6 alcohol stereospecifically, as
well as an assessment of the thermodynamic stability of the C-6
hydroxyl group, was of significant importance because indole
alkaloids are usually isolated by an acidic/basic extraction
INTRODUCTION
■
Indole alkaloids are of prominence because of the similarity with
tryptophan, which is an essential amino acid. The sarpagine
alkaloids contain the common structural element of the parent
pentacyclic sarpagan ring system1,2 with established stereo-
chemistry at C-3 (S), C-5 (R), and C-15 (R).2 The alkaloid er-
vincidine (Figure 1) belongs to the sarpagine class and has been
Figure 1. The indole alkaloid ervincidine.
isolated from the epigeal part of Vinca erecta Rgl. et Schmalh.3,4
The structure of ervincidine has six stereocenters, four of which
have the C-3 (S), C-5 (R), C-15 (R), and C-16 (R) configuration,
and contains a double bond at C(19)−C(20), which is usually
the thermodynamically less stable E configuration.
The stereochemistry of the alcohol function at the C-6 posi-
tion was not assigned by Glasby and Lounasmaa1,2,5 nor was the
location of the hydroxylmethyl at the C-16 group unequivocally
established. Yunusov et al.,3,4 who isolated this alkaloid, had
Received: December 4, 2013
Published: April 3, 2014
© 2014 American Chemical Society
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Scheme 1. General Approach to the Total Synthesis of the Ervincidine Diastereomer (Structural Assignment Proposed by Glasby
a1,2,5
and Lounasmaa et al.)
a
Reagents and conditions: (a) 1. CH3OCH2PPh3Cl (7.3 equiv), t-BuOK (7.9 equiv), benzene/THF; 2. 2 N aq HCl/THF, 55 °C, 90%. (b) NaBH4
(1.4 equiv), EtOH, 0 °C, 8 h, 90%. (c) TIPSCl, 2,6-lutidine, CH2Cl2, 0 °C, 90%. (d) IBX, EtOAc:DMSO (2:1), 80 °C, 8 h, 85%. (e) TBAF·H2O,
THF, 0 °C to rt, 85%. (f) CeCl3·7H2O, NaBH4, MeOH, −78 °C to rt, 90%.
process. In a retrosynthetic sense, the possible diastereomers 2
and 2′ as well as 3 and 3′ might be available via a common
intermediate, pentacyclic ketone 4. The chirality of 4 was to be
employed to introduce the correct stereocenters in the target
alkaloids 2, 2′ or 3, 3′.
combination with cerium chloride heptahydrate to afford the
final product 2. Reduction occurred stereospecifically to give the
β alcohol in 2 as a single diastereomer.16 The stereochemistry of
2 was confirmed using single-crystal X-ray structural analysis.
The optical rotation of this diastereomer 2 was determined to
be [α]2D6 +79° (c 0.6, MeOH), which was not in agreement with
the value reported in the literature.3−5 Hence, the diastereomer 2
was stirred in 0.2 N HCl at 0 °C. Examination by TLC (silica gel;
CH2Cl2:MeOH 9:1) indicated a new component at a lower
Rf value, which illustrated that complete epimerization of the
alcohol function at C-6 to diastereomer 2′ had occurred. Un-
fortunately, the new material could not be isolated due to the
small amount of the compound available. It appears that the C-6
α-hydroxyl group was, presumably, in the more stable α position
in epimeric alcohol 2′ based on this preliminary experiment.
To achieve the synthesis of the diastereomer with the C-16
hydroxymethyl function in the β position as proposed by Yunusov
et al.,3,4 pentacyclic ketone 4 was treated with triphenylphos-
phonium bromide in benzene in the presence of potassium
t-butoxide to afford diene 10 in 90% yield (Scheme 2).17 To
facilitate attack on diene 10 from the less hindered face of the
exocyclic methylene function and prevent hydroboration of the
C(19)−C(20) olefinic bond,18 9-BBN was chosen as the hydro-
borating agent. This was carried out under the standard con-
ditions with the Kabalka borate work up procedure19 to prohibit
Nb-oxidation. This was a key process because Nb-oxidation
oftentimes complicates this oxidation with H2O2.
RESULTS AND DISCUSSION
■
As illustrated in Scheme 1, ketone 4 was subjected to a Wittig
reaction with methoxymethyl triphenylphosphonium chloride in
the presence of anhydrous potassium tert-butoxide to provide a
mixture of two isomeric enol ethers (not shown) at C-16. After a
short wash column, the mixture of enol ethers was hydrolyzed
under acidic conditions to provide vellosimine 5 in 90% yield
(over two steps).6−9 The aldehyde function of 5 was then re-
duced with sodium borohydride to provide the alcohol nor-
macusine B (6), the spectral data of which are in complete
agreement with that of the natural product.7−10
The C-17 functionalized alcohol was then protected as the
triisopropylsilyl ether 7 employing 2,6-lutidine as the base to
provide the ether.7,8,10 Repeated attempts to oxidize the C-6
position of 7 with DDQ were unsuccessful. Finally, the oxidation
at the C-6 position was successfully accomplished using IBX at
80 °C11−14 to form the desired ketone 8.
Deprotection of the silyl group was accomplished using
TBAF/THF to provide the C-16 substituted alcohol 9, as shown
in Scheme 1. The selective reduction of the ketone 9 was car-
ried out via a Luche reduction15 using sodium borohydride in
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a3,4
Scheme 2. General Approach to the Total Synthesis of the Ervincidine Diastereomer
a
Reagents and conditions: (a) CH3PPh3Br (7.3 equiv), t-BuOK (7.9 equiv), benzene/THF, 90%. (b) 9-BBN (5 equiv), 0 °C to rt, 1.5 h; NaBO3·
4H2O, 0 °C to rt, 2 h, 70%. (c) TIPSCl, 2,6-lutidine, CH2Cl2, 90%. (d) IBX, EtOAc:DMSO (2:1), 80 °C, 8 h, 85%. (e) TBAF·H2O, THF, 90%.
(f) CeCl3·7H2O, NaBH4, MeOH, 90%.
a
Scheme 3. Synthesis of the C-6 α Diastereomer 3′ of Ervincidine
a
Reagents and conditions: (a) IBX, EtOAc: DMSO (2:1), 80 °C, 8 h, 80%. (b) THF, 9-BBN (5 equiv), 0 °C to rt, 1.5 h; NaBO3·4H2O, 0 °C to rt,
2 h, 70%.
The synthesis of TIPS derivative 12 was executed analogous to
the previous preparation20 from alcohol 11 in 90% yield. The
oxidation of the C-6 benzylic position to the ketone in 13 was
achieved by radical oxidation using IBX11−14 at 80 °C in 85%
yield.
was proposed that the attack took place from the exo (top) face
of the molecule. The boron could coordinate10 with the C-6
carbonyl oxygen atom as well as the Nb nitrogen atom, leading to
the formation of the α diastereomer 3′. This process was
executed, as shown in Scheme 3, in 70% yield. The optical
rotation of 3′ was [α]2D6 +17.00° (c 0.6, MeOH) and was not in
agreement with that reported in the literature for 3.3,4 It appears
that 9-BBN complexed10 with the Nb-nitrogen function and
blocked the attack from the bottom face of the ketone so that
excess 9-BBN could reduce the carbonyl group from the top face
to give α alcohol 3′.
As shown in Scheme 2, the silyl group from ketone 13 was
removed by treatment with TBAF in THF to give 14 in 90%
yield. The selective reduction of the ketone 14 was carried out
by Luche reduction15 to achieve the stereospecific synthesis of
the natural product ervincidine 3 with a β-hydroxyl group at
C-6 and the β-hydroxymethyl function at C-16 as a single dia-
stereomer in 90% yield. The optical rotation of 3 {[α]2D6 +29.00°
(c 0.6, MeOH)} was in excellent agreement with that reported in
the literature2−5 {[α]D26 +29.5° (c 0.6, MeOH)}, which com-
pleted the stereospecific total synthesis of the natural product
ervincidine 3 (Scheme 2). The structure and stereochemistry at
the C-6 and C-16 positions in 3 were established unequivocally
by NOESY and NOE NMR spectroscopy, including the absolute
configuration of the hydroxyl group at C-6, which is reported in
the Supporting Information.
The synthesis of the diastereomer with the opposite
stereochemistry to that of ervincidine 3 at the C-6 position was
also pursued (Scheme 3). Diene 10 was treated with IBX to give
ketone 15 at the C-6 position in 80% yield. In order to shorten
the synthetic route and also synthesize the other isomer, 9-BBN
was chosen, which reduced the C-6 keto group to the α alcohol
and also acted as a hydroborating agent at the C(16)−C(17)
olefinic bond.21,22 Since 9-BBN is a bulky hydroborating agent, it
CONCLUSION
■
In conclusion, the stereospecific total synthesis of ervincidine
3 has been accomplished from commercially available
D-(+)-tryptophan methyl ester 1, which served as both the chiral
auxiliary and the starting material. Moreover, this synthesis
unequivocally sets the correct stereochemistry of the hydroxyl
group at C-6 in a stereospecific fashion, as well as the β-C-16
hydroxymethyl group. The stereospecific conversion of D-(+)-
tryptophan methyl ester 1 into the key template pentacyclic
ketone 4 occurred via the asymmetric Pictet−Spengler reaction
(600 g scale), Dieckmann cyclization, and palladium-mediated
enolate cross-coupling reaction, which were the key steps to
synthesize these indole alkaloids. The Kabalka sodium borate
process worked much better than H2O2, as expected in this series.
The IBX-mediated oxidation and the Luche reduction afforded
the stereospecific total synthesis of ervincidine 3. Another
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removal of the solvent under reduced pressure, the residue was purified
by flash chromatography [CH2Cl2:MeOH (90:10)] to provide the
target diol 2 (13 mg, 90%); Rf 0.75 (silica gel, CH2Cl2/MeOH, 9:1);
[α]2D5 +79° (c 0.6 MeOH); [lit.3−5 [α]D22 = +29.5° (c 0.6 in CH3OH); 1H
NMR (300 MHz, CD3OD) δ 1.67 (d, 3H, J = 6.6 Hz), 1.80 (td, 1H,
J1 = 12.6 Hz, J2 = 6 Hz), 2.13 (m, 1H), 2.2 (m, 1H), 2.7 (t, 1H, J =
6.6 Hz), 3.01 (s, 1H), 3.5 (m, 3H), 3.6 (m, 2H), 4.10 (d, 1H, J = 8 Hz),
5.23 (d, 1H, J = 6 Hz), 5.47 (q, 1H, J = 6.6 Hz), 7.04 (m, 2H), 7.3 (d, 1H,
J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz); 13C NMR (75.5 MHz, CD3OD) δ
11.6, 27.2, 32.5, 39.2, 50.2, 55.6, 59.7, 63.8, 65.9, 102.3, 110.6, 116.9,
118.6, 119.2, 120.8, 126.5, 135.2, 136.9, 138.5; HRMS (ESI) m/z calcd
for C19H23N2O2 (M + H)+: 311.1760; found: 311.1758.
Preparation of (6S,11S,11aR,E)-9-Ethylidene-11-((triiso-
propylsilyl)oxy)methyl)-6,8,9,10,11,11a-hexahydro-6,10-
methanoindolo[3,2-b]quinolizin-12(5H)-one (13). The synthesis
of ketone 13 from TIPS derivative 12 was carried out analogous to the
preparation of 8 from 7 in 85% yield. 1H NMR (300 MHz, CDCl3) δ
0.96 (d, 21H, J = 2.7Hz), 1.66 (d, 3H, J = 7 Hz), 1.81 (t, 1H, J = 11 Hz),
2.06 (dd, 1H, J1 = 9.9 Hz, J2 = 3.3 Hz), 2.25 (m, 1H), 3.35 (d, 1H, J =
2 Hz), 3.47 (t, 1H, J = 11 Hz), 3.74 (d, 2H, J = 2.4 Hz), 3.78 (s, 1H), 3.84
(dd, 1H, J1 = 10.2 Hz, J2 = 4.8 Hz), 4.14 (dd, 1H, J1 = 10.5 Hz, J2 =
4.5 Hz), 5.32 (q, 1H, J = 6.9 Hz), 7.27 (m, 3H), 8.13 (d, 1H, J = 6.9 Hz),
8.9 (br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 11.9, 12.7, 17.9, 25.9,
27.8, 38.5, 50.1, 55.5, 59.9, 63.5, 108.6, 111.3, 114.3, 121.8, 122.8, 123.5,
123.9, 135.7, 139.2, 155.3, 191.5; HRMS (ESI) m/z calcd for
C28H41N2O2Si (M + H)+: 465.2937; found: 465.2914. This material
was employed directly in the next step.
important study was the epimerization of the C-6 alcohol with
0.2 N HCl, which indicated that care must be employed in the
isolation of these alkaloids that contain a benzylic hydroxyl
group. The research process developed here also provides a
general entry into C-6 hydroxy-substituted indole alkaloids with
either the α or the β configuration. The structures of the
diastereomers were also unequivocally assigned by employing X-
ray analysis on 2 and detailed high-resolution, NOESY and NOE
studies and then compared to those on 2. This research corrects
the errors in Glasby’s book1 and Lounasmaa et al.’s review5 and
clarifies the work of Yunusov et al. as well as providing the correct
absolute configuration of the C-6 hydroxyl function in
ervincidine 3.3,4
EXPERIMENTAL SECTION
■
IBX-Mediated Oxidation To Provide (6S,11S,11aR,E)-9-Ethyl-
idene-11-((triisopropylsilyl)oxy)methyl)-6,8,9,10,11,11a-hexa-
hydro-6,10-methanoindolo[3,2-b]quinolizin-12(5H)-one
(8).11−14 To a solution of triisopropylsilyl ether 7 (100 mg, 0.22 mmol)
in EtOAc/DMSO (10 mL/5 mL) was added IBX (0.552 g,
0.88 mmol) in one portion at rt. The mixture that resulted was heated
and stirred at 80 °C overnight, and the reaction progress was monitored
by TLC (silica gel, EtOAc). The reaction mixture was cooled to 0 °C and
quenched with a saturated solution of aq NaHCO3 (4 mL), followed by
treatment with a saturated solution of aq Na2S2O3 (5 mL). After this, the
mixture was stirred for an additional 10 min at 0 °C. The aq layer was
extracted with additional amounts of EtOAc (3 × 10 mL), and the
combined organic layers were washed with brine (10 mL) and dried
(K2CO3). The solvent was removed under reduced pressure to provide
the crude oil, which was purified by flash chromatography [silica gel,
hexane:EtOAc (1:1)] to provide the benzylic ketone 8 (87 mg, 85%). 1H
NMR (300 MHz, CDCl3) δ 0.94 (s, 21H), 1.66 (d, 3H, J = 6.3 Hz), 1.82
(d, 1H, J = 6.3 Hz), 2.13 (t, 2H, J = 9.9 Hz), 2.86 (d, 1H, J = 7 Hz), 3.17
(s, 1H), 3.5 (m, 3H), 3.8 (dd, 1H, J1 = 9.6 Hz, J2 = 4.2 Hz), 4.2 (d, 1H, J =
8.4 Hz), 5.4 (q, 1H, J = 7 Hz), 7.14 (m, 3H), 8.07 (d, 1H, J = 7.2 Hz),
9.03 (br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 11.9, 12.9, 18.0, 29.7,
32.5, 42.6, 50.5, 54.8, 63.9, 64.6, 106.5, 111.6, 118.5, 121.6, 122.7, 123.6,
124.5, 132.3, 136.1, 154.7, 192.0; HRMS (ESI) m/z calcd for
C28H41N2O2Si (M + H)+ 465.2937; found: 465.2950.
Preparation of (6S,11S,11aR,E)-9-Ethylidene-11-(hydroxy-
methyl)-6,8,9,10,11,11a-hexahydro-6,10-methanoindolo[3,2-
b]quinolizin-12(5H)-one (14). The synthesis of monol 14 from TIPS
derivative 13 was carried out analogous to the preparation of 9 from 8 in
90% yield. 1H NMR (300 MHz, CD3OD) δ 1.68 (td, 3H, J1 = 6.6 Hz,
J2 = 3.9 Hz), 2.06 (m, 4H), 2.26 (m, 1H), 3.3 (m, 1H), 3.67 (dd, 1H, J1 =
11 Hz, J2 = 5 Hz), 3.77 (m, 3H), 4.28 (dd, 1H, J1 = 11 Hz, J2 = 5 Hz), 5.4
(q, 1H, J = 6 Hz), 7.27 (m, 2H), 7.47 (m, 1H), 8.01 (m, 1H); 13C NMR
(75.5 MHz, CD3OD) δ 11.5, 24.8, 27.6, 38.1, 49.5, 54.6, 58.3, 63.2,
107.6, 111.6, 114.4, 120.6, 122.4, 123.3, 123.5, 136.7, 138.2, 156.3,
191.8; HRMS (ESI) m/z calcd for C19H21N2O2 (M + H)+: 309.1603;
found: 309.1588. This material was employed directly in the next step.
Preparation of Ervincidine [(6S,11S,11aR,12R,E)-9-ethyl-
idene-11-(hydroxymethyl)-5,6,8,9,10,11,11a,12-octahydro-
6,10-methanoindolo[3,2-b]quinolizin-12-ol (3)]. The synthesis of
3 from 14 was carried out analogous to the preparation of 2 from 9 in
90% yield. Rf 0.71 (silica gel, CH2Cl2/MeOH, 9:1); [α]2D5 +29.0° (c 0.6
Synthesis of (6S,11R,11aR,E)-9-Ethylidene-11-(hydroxy-
methyl)-6,8,9,10,11,11a-hexahydro-6,10-methanoindolo[3,2-
b]quinolizin-12(5H)-one (9). A solution of benzylic ketone 8 (20 mg,
0.043 mmol) was stirred in THF (1 mL) in a 5 mL round-bottom flask.
At 0 °C, excess TBAF hydrate was then added to the mixture, and it was
allowed to warm to rt. The reaction mixture was stirred for 2 h until
analysis of the mixture by TLC indicated the absence of starting material.
The reaction was quenched with water (10 mL) and extracted with
EtOAc (3 × 10 mL), washed with brine, and dried (Na2SO4). After
removal of the solvent under reduced pressure, the residue was purified
by flash chromatography [EtOAc:hexane (4:1)] to provide the target
monol 9 (11 mg, 85%). 1H NMR (300 MHz, CD3OD) δ 1.68 (d, 3H, J =
6 Hz), 1.87 (d, 1H, J = 12 Hz), 2.12 (br, 1H), 2.28 (t, 1H, J = 12 Hz),
2.84 (d, 1H, J = 6 Hz), 3.25 (s, 1H), 3.66 (m, 5H), 4.35 (dd, 1H, J1 =
9 Hz, J2 = 3 Hz), 5.55 (q, 1H, J = 7.5 Hz), 7.25 (m, 2H), 7.43 (d, 1H, J =
7 Hz), 7.98 (d, 1H, J = 8.4 Hz); 13C NMR (75.5 MHz, CD3OD) δ 11.6,
19.3, 29.2, 42.6, 50.2, 54.4, 63.2, 64.3, 105.4, 111.6, 117.9, 120.5, 122.2,
123.2, 124.3, 133.3, 136.8, 156.4, 193.7; HRMS (ESI) m/z calcd for
C19H21N2O2 (M + H)+: 309.1603; found: 309.1588. This material was
used directly in a later step.
Preparation of (6S,11R,11aR,12R,E)-9-Ethylidene-11-
(hydroxymethyl)-5,6,8,9,10,11,11a,12-octahydro-6,10-
methanoindolo[3,2-b]quinolizin-12-ol (2). A solution of alcohol 9
(15 mg, 0.049 mmol) was stirred in MeOH (1 mL) in a 5 mL flask.
At −78 °C, CeCl3·7H20 (19 mg, 0.054 mmol) and NaBH4 (2 mg,
0.049 mmol) were added to the mixture, and it was allowed to warm to
rt. The reaction mixture was stirred for 3 h until analysis of the mixture
by TLC (silica gel) indicated the absence of starting material. The
reaction was quenched with aq NH4Cl (5 mL) and extracted with
CH2Cl2 (3 × 10 mL), washed with brine, and dried (Na2SO4). After
in MeOH); [lit.3−5 [α]D22 = +29.5° (c 0.6 in CH3OH)]; H NMR
1
(300 MHz, CD3OD) δ 1.70 (d, 3H, J = 6.9 Hz), 1.94 (m, 2H), 2.26 (m,
1H), 2.9 (q, 1H, J = 2.4 Hz), 3.14 (dd, 1H, J1 = 11.4 Hz, J2 = 6 Hz), 3.61
(dd, 1H, J1 = 10 Hz, J2 = 5.4 Hz), 3.6 (s, 3H), 3.8 (m, 1H), 4.2 (dd, 1H,
J1 = 8.4 Hz, J2 = 4 Hz), 5.4 (m, 2H), 7.0 (t, 1H, J = 7 Hz), 7.08 (t, 1H, J =
7 Hz), 7.32 (d, 1H, J = 8.1 Hz), 7.76 (d, 1H, J = 7.8 Hz); 13C NMR
(75.5 MHz, CD3OD) δ 11.5, 26.3, 28.1, 42.5, 50.1, 55.7, 58.7, 61.0, 67.3,
110.2, 110.6, 114.2, 118.6, 119.7, 120.8, 125.0, 136.2, 136.9, 138.9;
HRMS (ESI) m/z calcd for C19H23N2O2 (M + H)+: 311.1760; found:
311.1773. The optical rotation and mass spectrum were in excellent
agreement with the natural product.3,4
Synthesis of (6S,11aR,E)-9-Ethylidene-11-methylene-6,8,9,
10,11,11a-hexahydro-6,10-methanoindolo[3,2-b]quinolizin-
12(5H)-one (15). To a solution of diene 10 (100 mg, 0.36 mmol) in
EtOAc/DMSO (5 mL/2.5 mL) was added IBX (0.9 g, 1.44 mmol)
in one portion at rt. The mixture was heated and stirred at 80 °C
overnight, and the reaction progress was monitored by TLC (silica gel,
EtOAc). The reaction mixture was cooled to 0 °C and quenched with a
saturated solution of aq NaHCO3 (4 mL), followed by treatment with a
saturated solution of aq Na2S2O3 (5 mL). After this, the mixture was
stirred for an additional 10 min at 0 °C. The aq layer was extracted with
additional amounts of EtOAc (3 × 10 mL), and the combined organic
layers were washed with brine (10 mL) and dried (K2CO3). The solvent
was removed under reduced pressure to provide the crude oil, which was
purified by chromatography [silica gel, hexane:EtOAc (3:1)] to provide
the benzylic ketone 15 (84 mg, 80%). 1H NMR (300 MHz, CD3OD)
1.66 (d, 3H, J = 6 Hz), 1.9 (m, 1H), 2.36 (m, 1H), 3.6 (m, 3H), 4.0
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The Journal of Organic Chemistry
Article
(m, 1H), 4.9 (d, 1H, J = 2 Hz), 5.0 (d, 1H, J = 2 Hz), 5.39 (q, 1H, J =
6.8 Hz), 7.27 (m, 2H), 7.4 (m, 1H), 7.6 (m, 2H), 8.0 (m, 1H); 13C NMR
(75.5 MHz, CD3OD) δ 11.1, 34.4, 38.5, 50.1, 54.4, 67.4, 105.9, 106.2,
124.3, 128.5, 128. 6, 131.6, 131.7, 132.4, 135.7, 136.7, 145.1, 155.9,
190.2; HRMS (ESI) m/z calcd for C19H19N2O (M + H)+: 291.1497;
found: 291.1513. This material was employed directly in the next step.
Preparation of (6S,11S,11aR,12S,E)-9-Ethylidene-11-(hydroxy-
methyl)-5,6,8,9,10,11,11a,12-octahydro-6,10-methanoindolo-
[3,2-b]quinolizin-12-ol (3′). To a solution of olefin 15 (100 mg,
0.344 mmol) in THF (10 mL) was added 9-BBN (0.5 M in THF,
3.44 mL, 1.72 mmol) dropwise, at 0 °C. The solution was allowed to
warm to rt and stirred for 1.5 h. The reaction mixture was then cooled to
0 °C, and NaBO3·4H2O (0.795 g, 5.16 mmol) was added, and the
reaction temperature was allowed to warm to rt. The mixture that
resulted was stirred for 2 h at rt, diluted with CH2Cl2 (50 mL), washed
with H2O (3 × 50 mL) as well as brine (50 mL), and dried (K2CO3).
The solvent was removed under reduced pressure, and the residue was
chromatographed (silica gel, CH2Cl2/MeOH; 9:1) to provide alcohol 3′
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(16) ORTEP view of the crystal structure of 2. CCDC 942158 (2) and
CCDC 965610 (9) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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298.
(74 mg, 70% yield). Rf 0.73 (silica gel, CH2Cl2/CH3OH, 9:1); [α]D25
=
+17.0° (c 0.6 in CH3OH); [lit.3−5 [α]D22 = +29.5° (c 0.6 in CH3OH)]; 1H
NMR (300 MHz, CD3OD) δ 1.70 (d, 3H, J = 6 Hz), 1.8 (m, 3H), 1.92
(m, 2H), 2.27 (m, 1H), 2.9 (s, 1H), 3.16 (dd, 1H, J1 = 11.4 Hz, J2 =
6 Hz), 3.61 (m, 3H), 3.8 (m, 1H), 4.2 (m, 1H), 5.3 (q, 1H, J = 6.6 Hz),
5.36 (d, 1H, J = 4.8 Hz), 7.0 (m, 2H), 7.35 (s, 1H), 7.82 (d, 1H, J =
7.5 Hz); 13C NMR (75.5 MHz, CD3OD) δ 11.5, 26.3, 28.2, 42.6, 50.1,
55.7, 58.7, 61.1, 67.4, 110.2, 110.6, 114.1, 118.6, 119.7, 120.8, 125.1,
136.3, 136.9, 139.1; HRMS (ESI) m/z calcd for C19H23N2O2 (M + H)+:
311.1760; found: 311.1748
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ASSOCIATED CONTENT
* Supporting Information
■
S
Spectral data for all new compounds including X-ray data for 9
and 2. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: capncook@uwm.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We wish to acknowledge the NIMH (in part) and the Lynde and
Harry Bradley Foundation for support of this work. X-ray
crystallographic studies were carried out at the Naval Research
Laboratory and supported by NIDA-NRL Interagency Agree-
ment Number Y1-DA1101.
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